The Recombinant T Cell Receptor Strategy: Insights into Structure and Function of Recombinant Immunoreceptors on the Way Towards an Optimal Receptor Design for Cellular Immunotherapy

Abstract:

A promising approach in adoptive immunotherapy is based on the induction of a specific cellular anti-tumor response by antigen-specific, cytolytic T cells. Due to difficulties in isolating tumor-specific T cells in sufficient amounts, it was proposed to graft cytolytic T cells with an antigen-specific, recombinant T cell receptor. The antigen binding domain of the receptor consists of a single-chain antibody fragment (scFv) that is derived from a monoclonal antibody and binds to a tumor associated antigen. The intracellular signalling domain is derived from the cytoplasmic part of a membrane bound receptor to induce cellular activation, e.g., the FceRI receptor γ-chain or the CD3 ζ-chain. By use of this type of recombinant receptor, the strategy combines the advantages of MHC-independent, antibody-based antigen binding with efficient T cell activation upon specific binding to the receptor ligand. The modular composition of the receptor, moreover, facilitates modification of both the antigen b inding and signalling properties. Accordingly, we and others have generated a panel of recombinant T cell receptors with specificities for malignantly or virally transformed cells. Receptor grafted effector cells were demonstrated to mediate a highly efficient immune response towards antigen expressing target cells. However, little is known about the impact of the recombinant receptor modules on recognition of highly heterologous target antigens and on cellular activation in a complex immunological context. This review summarizes the current knowledge about the generation and function of recombinant immunoreceptors and discusses the limitations and perspectives of the methodology for use in cellular immunotherapy.

Abstract: A promising approach in adoptive immunotherapy is based on the induction of a specific cellular anti-tumor response by antigen-specific, cytolytic T cells. Due to difficulties in isolating tumor-specific T cells in sufficient amounts, it was proposed to graft cytolytic T cells with an antigen-specific, recombinant T cell receptor. The antigen binding domain of the receptor consists of a single-chain antibody fragment (scFv) that is derived from a monoclonal antibody and binds to a tumor associated antigen. The intracellular signalling domain is derived from the cytoplasmic part of a membrane bound receptor to induce cellular activation, e.g., the FceRI receptor γ-chain or the CD3 ζ-chain. By use of this type of recombinant receptor, the strategy combines the advantages of MHC-independent, antibody-based antigen binding with efficient T cell activation upon specific binding to the receptor ligand. The modular composition of the receptor, moreover, facilitates modification of both the antigen b inding and signalling properties. Accordingly, we and others have generated a panel of recombinant T cell receptors with specificities for malignantly or virally transformed cells. Receptor grafted effector cells were demonstrated to mediate a highly efficient immune response towards antigen expressing target cells. However, little is known about the impact of the recombinant receptor modules on recognition of highly heterologous target antigens and on cellular activation in a complex immunological context. This review summarizes the current knowledge about the generation and function of recombinant immunoreceptors and discusses the limitations and perspectives of the methodology for use in cellular immunotherapy.